Salinosporamide A (1) was recently discovered by Fenical et al. as a bioactive product of a marine microorganism that is widely distributed in ocean sediments. See, Feeling et al., Angew. Chem. Int. Ed., 2003, 42, 355-357.

Structurally Salinosporamide A closely resembles the terrestrial microbial product Omuralide (2a) that was synthesized by Corey et al. several years ago and demonstrated to be a potent inhibitor of proteasome function. See, (a) Corey et al., Chem. Pharm. Bull., 1999, 47, 1-10; (b) Corey et al., Tetrahedron Lett., 1993, 34, 6977-6980; (c) Corey et al., J. Am. Chem. Soc., 1992, 114, 10677-10678; and (d) Fenteany et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 3358-3362.
A simple and effective stereocontrolled synthesis of Salinosporamide A is taught in commonly owned, copending U.S. patent application Ser. No. 10/821,621, filed 9 Apr. 2004. The process described therein is capable of providing Salinosporamide A, and with minor modifications, is likewise capable of providing compounds of the present invention. The relevant portions of that disclosure are presented below.
Like Omuralide, Salinosporamide A inhibits the proteasome, an intracellular enzyme complex that destroys proteins the cell no longer needs. Without the proteasome, proteins would build up and clog cellular machinery. Fast-growing cancer cells make especially heavy use of the proteasome, so thwarting its action is a compelling drug strategy. See, Fenical et al., U.S. Patent Publication No. 2003-0157695A1, the disclosure of which is hereby incorporated herein by reference.
Omuralide is generated by β-lactonization of the N-acetylcysteine thiolester lactacystin (2b) that was first isolated by the Omura group as a result of microbial screening for nerve growth factor-like activity. See, Omura et al., J. Antibiot., 1991, 44, 113-116; and Omura et al., J. Antibiot., 1991, 44, 117-118.
Methods for preparing lactacystin and related compounds, including analogs of lactacystin and clasto-lactacystin beta-lactone, are taught in the following references; U.S. Pat. Nos. 6,645,999; 6,566,553; 6,458,825; 6,335,358; 6,294,560; 6,214,862; 6,147,223; 6,133,308; 5,869,675; 5,756,764; and PCT Publication No. WO 96/32105; the disclosures of which are hereby incorporated herein by reference. See also, (a) Corey et al., Total Synthesis of Lactacystin, J. Am. Chem. Soc., 1992, 114, 10677-10678; (b) Corey et al., An Enantioselective Synthesis of (6R)-Lactacystin, Tetrahedron Lett., 1993, 34, 6969-6972; (c) Corey et al., Synthesis of (6R, 7S)-Lactacystin and 6-Deoxy-lactacystin from a Common Intermediate, Tetrahedron Lett., 1993, 34, 6973-6975; and (d) Corey et al., Total Synthesis of Lactacystin: An Enantioselective Synthesis of (6R)-Lactacystin: Total Synthesis of (+)-Lactacystin, . . . , Chemtracts-Organic Chemistry, pp. 266-272, 1994.